Type 1 diabetes afflicts more than 1.5 million people in the United States with 30,000 additional cases diagnosed each year. It is caused by autoimmune destruction of the insulin-producing pancreatic islet cells. Replacement of these cells can be accomplished safely by direct transplantation of islet cells from a donor pancreas, however the dependence on this inadequate supply of donor islets will continue to limit its broad application. This shortfall could be remedied by the utilization of islets from alternate sources, the most promising of which is the pig. Studies from our laboratory and other groups have demonstrated prolonged survival of neonatal porcine islets infused into diabetic non-human primates (NHPs) with reversal of their hyperglycemia. Nevertheless, there remain a number of immunologic and technical challenges that must be solved before porcine islet xenotransplantation becomes a clinical reality. The following criteria are essential for successful clinical porcine islet xenotransplantation: 1) the treatment agents must be readily available, with minimal side effects, 2) genetic manipulation of pigs and ex vivo treatment of islets must be optimized to minimize interaction with the human immune system, and 3) mechanisms unique to cellular transplantation that lead to porcine islet loss must be defined and controlled. Our extensive experience in this field has led us to develop a comprehensive translational strategy addressing these concerns to bring this potential therapy to clinical reality. Three Aims serve as the foundation for our translational strategy. Our approach is centered on proven techniques that are standard practice within our collaborative partnership, enabling us to pursue truly novel investigations with practical design. The proposed independent but interrelated studies provide us an opportunity to investigate each concurrently. We will refine clinically available immunosuppression with a proven and extensively used diabetic preclinical model. Also imperative to clinical translation is identification of the ideal porcine islet donor, using the ual transplant model we have developed to fulfill this purpose. We will work to define potential extrinsic and intrinsic islet modifications that may improve graft survival and function. We will also further elucidate the intrinsic NFKB-driven inflammation and programmed cell death pathways that are integral to the process of islet engraftment and survival. These studies aim to overcome barriers remaining to clinical application of islet xenotransplantation and advance the field of xenotransplantation.